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Pentamer

O J chain

Naive B cell antigen receptor, complement activation

The effector functions of antibodies are discussed in detail in Chapter 12.

In humans, about 60% of antibody molecules have k light chains and about 40% have X light chains. Marked changes in this ratio can occur in patients with B cell tumors because the many neoplastic cells, being derived from one B cell clone, produce a single species of antibody molecules, all with the same light chain. In fact, a skewed ratio of K-bearing cells to X-bearing cells is often used clinically in the diagnosis of B cell lymphomas. In mice, K-containing antibodies are about 10 times more abundant than X-containing antibodies. Unlike in heavy chain isotypes, there are no known differences in function between K-containing antibodies and X-containing antibodies.

Secreted and membrane-associated antibodies differ in the amino acid sequence of the carboxyl-terminal end of the heavy chain C region. In the secreted form, found in blood and other extracellular fluids, the carboxyl-terminal portion is hydrophilic. The membrane-bound form of antibody contains a carboxyl-terminal stretch that includes a hydrophobic a-helical transmembrane anchor region followed by an intracellular juxtamembrane positively charged stretch that helps anchor the protein in the membrane (Fig. 5-8). In membrane IgM and IgD molecules, the cytoplasmic portion of the heavy chain is short, only three amino acid residues in length; in membrane IgG and IgE molecules, it is somewhat longer, up to 30 amino acid residues in length.

Secreted IgG and IgE and all membrane Ig molecules, regardless of isotype, are monomeric with respect to the basic antibody structural unit (i.e., they contain two heavy chains and two light chains). In contrast, the secreted forms of IgM and IgA form multimeric complexes in which two or more of the four-chain core antibody structural units are covalently joined. IgM may be secreted as pen-tamers and hexamers of the core four-chain structure, whereas IgA is often secreted as a dimer. These complexes are formed by interactions between regions, called tail pieces, that are located at the carboxyl-terminal ends of the secreted forms of |i and a heavy chains (see Table 5-2). Multimeric IgM and IgA molecules also contain an additional 15-kD polypeptide called the joining (J) chain, which is disulfide bonded to the tail pieces and serves to

FIGURE 5-8 Membrane and secreted forms of Ig heavy chains. The membrane forms of the Ig heavy chains, but not the secreted forms, contain transmembrane regions made up of hydropho-bic amino acid residues and cytoplasmic domains that differ significantly among the different isotypes. The cytoplasmic portion of the membrane form of the |i chain contains only three residues, whereas the cytoplasmic region of IgG heavy chains contains 20 to 30 residues. The secreted forms of the antibodies end in C-terminal tail pieces, which also differ among isotypes: | has a long tail piece (21 residues) that is involved in pentamer formation, whereas IgGs have a short tail piece (3 residues).

FIGURE 5-8 Membrane and secreted forms of Ig heavy chains. The membrane forms of the Ig heavy chains, but not the secreted forms, contain transmembrane regions made up of hydropho-bic amino acid residues and cytoplasmic domains that differ significantly among the different isotypes. The cytoplasmic portion of the membrane form of the |i chain contains only three residues, whereas the cytoplasmic region of IgG heavy chains contains 20 to 30 residues. The secreted forms of the antibodies end in C-terminal tail pieces, which also differ among isotypes: | has a long tail piece (21 residues) that is involved in pentamer formation, whereas IgGs have a short tail piece (3 residues).

stabilize the multimeric complexes and to transport multimers across epithelia from the basolateral to the luminal end. As we shall see later, multimeric forms of antibodies bind to antigens more avidly than monomeric forms do, even if both types of antibody contain Fab fragments that individually bind the antigen equally well.

Antibodies of different species differ from one another in the C regions and in framework parts of the V regions. Therefore, when Ig molecules from one species are introduced into another (e.g., horse serum antibodies or mouse monoclonal antibodies injected into humans), the recipient mounts an immune response and makes antibodies largely against the C regions of the introduced Ig. The response often creates an illness called serum sickness (see Chapter 18) and thus greatly limits the ability to treat individuals with antibodies produced in other species. Much effort has been devoted to overcoming this problem with monoclonal antibodies, and this issue is discussed in more depth later. Smaller sequence differences are present in antibodies from different individuals even of the same species, reflecting inherited polymorphisms in the genes encoding the C regions of Ig heavy and light chains. When a polymorphic variant found in some individuals of a species can be recognized by an antibody, the variants are referred to as allotypes, and the antibody that recognizes an allotypic determinant is called an anti-allotypic antibody. The differences between antibody V regions map to CDRs and constitute the idio-types of antibodies. An antibody that recognizes some aspect of the CDRs of another antibody is therefore called an anti-idiotypic antibody. There have been interesting theories that individuals produce anti-idiotypic antibodies against their own antibodies that control immune responses, but there is little evidence to support the importance of this potential mechanism of immune regulation.

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